Prostate cancer is the most commonly diagnosed cancer in males. However, the molecular mechanisms responsible for its development remain unknown. One of the unique characteristics of prostate adenocarcinoma is that the clinically recognized cancers represent only a small minority of the ones present in histological sections at autopsies. Thus, dysregulation of prostate growth appears to be an extremely common cellular event, while rapid and metastatic growth is less common and may depend on additional local or systemic factors. It is as yet unknown what endogenous or systemic factors regulate this phenomenon. We propose to investigate the role of the insulin-like growth factors (IGFs), their receptors and binding proteins (IGFBPs) in the process of prostate carcinogenesis. The IGFs are important mitogenic factors that have been shown to have autocrine-paracrine, as well as endocrine roles in normal and malignant cellular growth. We plan to characterize multiple aspects of the IGF system in prostate cancer, to identify and analyze specific alterations in the circulating IGFs and IGFBPs in the sera of humans with prostate cancer and in an animal model of prostate cancer, and to investigate the possibility that the proteolytic action of prostate specific antigen on IGFBPs is a growth stimulant in prostate cancer. Our resources include an established 3 year collaboration between scientists with expertise in the molecular biology and biochemistry of the insulin-like growth factors, the cell biology of cultured prostatic cells, the biochemistry of prostate specific antigen and in clinical urology, which have already produced a number of contributions to our understanding of prostate cancer. We believe that a thorough analysis of the role of the IGFs in prostatic cell growth will result in important insights into the fundamental regulation of prostatic carcinogenesis, and provide potentially valuable diagnostic and therapeutic findings.